Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Unfortunately, this disease is often diagnosed at a late incurable stage, with less than 5% of patients surviving 5 years. Antiangiogenic therapy has not been well studied in this disease. The first specific aim of this study will help define the role of treatment with angiogenesis inhibitors in a mouse model of pancreatic cancer that closely resembles human disease. In specific aim 1 I will look at different combinations of antiangiogenic agents. Adenoassociated virus will be used to deliver novel antiangiogenic agents. Combinations of antiangiogenic agents and the chemotherapeutic agent, Gemcitabine, will also be tested. Preliminary data points to the importance of apoptosis during antiangiogenic therapy with recombinant Type I repeats of TSP-1 (TSR) in this model of pancreatic cancer. Therefore, in specific aim 2 the molecular mechanisms of the signal transduction pathways that are involved in mediating apoptosis by TSP-1 will be analyzed. Completion of this mentored project will allow me to gain in-depth expertise in areas such as novel delivery mechanisms such as gene therapy, detailed analysis of apoptotic pathways focusing on endothelial and tumor cell responses to antiangiogenic agents. This unique combination will allow me to complete the first phase of my career development and progress on to independent research.